Download Phase-I - Moodle Lille 2

Produit physique
Information et
Engagement de résultat
1/Un « produit physique»
-A-Substance active
-B-Formulation galénique
-C-Emballage
2
2/ Une « documentation »
établie au cours des différentes phases d’essais cliniques
 elle permet d’obtenir l’autorisation de mise sur le marché
 elle sert de base à l’information du prescripteur
 elle sert à démontrer aux organismes payeurs le service médical
rendu et son amélioration.
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Un médicament est un « produit »
-1-Substance active
-2-Formulation galénique
-3-Emballage
4
Drug substance (Active pharmaceutical ingredient) API
Drug product (Dosage form; Finished product)
La Substance active
1. Substance ayant un effet pharmacologique susceptible de se
traduire par une application thérapeutique
2. Substance pouvant être produite sous forme pure à grande
échelle, de manière reproductible et économiquement et
écologiquement viable
3. Substance susceptible d’être dosée ainsi que ses impuretés, ses
produits de dégradation et ses métabolites
4. Toxique potentiel
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1. Une substance ayant un effet pharmacologique susceptible de se
traduire par une application thérapeutique
7
Le venin de serpent contient des substances ayant de puissants
effets pharmacologiques
AnCrod/ Virpinex est une protéase à
sérine préparée à partir du venin
d’une vipère qui permet de lyser les
caillots formés lors d’un accident
cérébrovasculaire
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1. Une substance ayant un effet pharmacologique susceptible de se
traduire par une application thérapeutique
a. Dans le prolongement des essais pharmacologiques de
discovery, il faudra montrer l’efficacité du principe actif dans des
modèles animaux de la pathologie ciblée
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Modèle animal d’obésité
Modèle animal de migraine
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1. Une substance ayant un effet pharmacologique susceptible de se
traduire par une application thérapeutique
a. Dans le prolongement des essais pharmacologiques de
discovery, il faudra montrer l’efficacité du principe actif dans des
modèles animaux de la pathologie ciblée
b. Pour la mise en place des essais cliniques il faudra générer
une relation dose-réponse entre la quantité administrée et
l’effet pharmacologique et déterminer une durée d’action.
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relation dose-réponse entre la quantité
administrée et l’effet pharmacologique
12
2. Une substance pouvant être produite
a. pure, de qualité constante et de stabilité suffisante.
b. de manière reproductible (y compris les impuretés). La voie
de synthèse sera souvent très différente de celle suivie lors de
la découverte.
c. à grande échelle, de manière reproductible et
économiquement et écologiquement viable
13
En 1995, apparait sur le marché le Saquinavir, le
premier inhibiteur de la protéase du virus du sida
Il est suivi en 1996, par un second médicament de la
même classe thérapeutique: le Ritonavir (Norvir) qui
est commercialisé sous la forme d’une solution buvable
dosée à 80 mg/mL
Les résultats sont spectaculaires 
En 1998, une nouvelle forme cristalline très
peu soluble commença à précipiter dans
les flacons de Ritonavir (Norvir), menaçant
d’entrainer un arrêt de la production.
170 mg/mL
20 mg/mL
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3. Une substance susceptible d’être dosée au moyen de méthodes
analytiques qui:
a. Devront permettre de doser le principe actif
- dans les fluides physiologiques
- dans les formulations
b. Devront faire l’objet d’une validation.
c. Devront aussi permettre le dosage
- des impuretés produites lors de la fabrication et du
vieillissement
- des métabolites détectés lors des études de
pharmacocinétique.
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Métabolisme Hépatique du Ritonavir
Structure des Onze Principaux Métabolites
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Métabolisme Hépatique du Ritonavir
identification des Onze Principaux Métabolites par Chromatographie
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4. Un principe actif est un toxique potentiel qu’il faudra évaluer:
a. Tests cellulaires de mutagénicité et de génotoxicité.
b. Toxicité aigue après une dose unique ou sur une période de 24 heures
c.
Toxicité sub-aigue selon un régime qui reflète l’application clinique envisagée.
Réalisée sur deux espèces dont un non-rongeur.
d. Toxicité chronique, sur une période dépassant 6 mois permet d’évaluer les risques
associés à l’usage prolongé de la substance.
e. Carcinogénicité : généralement sur des rongeurs pendant 2 ans.
f.
Incidence sur la fertilité, tératogénicité, développement post-natal
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Marge Thérapeutique
relation dose-réponse entre la quantité
administrée et l’effet pharmacologique
20
La Forme Galénique
1. C’est la forme sous laquelle sera administré la substance active
(comprimé, gélule, solution injectable, aérosol ….)
2. Des formes simplifiées seront utilisées au cours des premiers essais
cliniques (ex. des gélules remplies manuellement).
Elles doivent être stable pendant la durée des essais.
3. La forme définitive sera développée durant les essais de phase I et II
et adoptée lors des essais de phase III.
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2/ Une « documentation »
Etablie au cours des différentes phases d’essais cliniques
 elle permet d’obtenir l’autorisation de mise sur le marché
 elle sert de base à l’information du prescripteur et du patient
 elle sert à démontrer aux organismes payeurs le service
médical rendu et son amélioration.
23
La documentation comprend les informations suivantes
- Pharmacologie clinique
- Indication(s) thérapeutiques
- Contre-indications
- Précautions
- Effets secondaires
- Dosage et administration
- Interactions Médicamenteuses ….
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Fabrication du
Produit physique
Information et
Engagement de résultat
Cost of Good Sold / Sales
Generics
Brand Name
Biologics
J Pharm Innov (2008) 3:30–40
Brand Name ~ 27%
Biologics ~ 13%
Fabrication du
Produit physique
Brand Name ~ 73% Information et
Biologics ~ 87%
Engagement de résultat
Link disease
and target.
Hits
confirmation
Potency
Pharmacological
profile
20-100 people
100-500 people
1000-10000 people
Safety
Efficacy
Efficiency
PK/ ADME
Administration
route
Dose ranging
Safety
Tox properties
Preclinical tox
Safety
Full SAR
D/D Interactions
Selectivity
Hit generation:
HTS
rational design
In silico screen
Potency
Cytotoxicity
Preliminary
animal efficacy
Initial SAR
Les “informations” sont acquises aux cours des phases précliniques et cliniques
Costs to discover and develop a new molecular entity
p(TS): probability of
technical success
WIP: work in process
NATURE Drug Discovery vol 9 | March 2010 | 203
Costs to discover and develop a new molecular entity
NATURE Drug Discovery vol 9 | March 2010 | 203
R&D cost
Treatment Cost per patient =
Number of patients
10.000.000 patients
+ Cost of Production + MG&A
For one Treatment
1000 millions
= 100 $
Blockbuster Model
= 40.000 $
Orphan Drug Model
10.000.000
400 millions $
10.000 patients
10.000
34
The Shift to High-Priced Innovator Drugs in the USA
http://www.evaluategroup.com/public/EvaluatePharma-Free-Access.aspx
35
The Shift to High-Priced Innovator Drugs in the USA
http://www.evaluategroup.com/public/EvaluatePharma-Free-Access.aspx
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Clinical Development of a new molecular entity
NATURE Drug Discovery vol 9 | March 2010 | 203
the drug development process is divided into six distinct
phases:
 Regulatory preclinical studies
 Phase-Ia
 Phase-Ib
 Phase-IIa
 Phase-IIb
 Phase-III
The preclinical phase :
 The preclinical phase is defined as the phase
 from the first good laboratory practice (GLP) toxicology dose (at least two mammalian species), prior
to human trials authorization through
 to an investigational new drug (IND, US) application or first clinical trial application (CTA, EU) before
first-in-human (FIH) testing.
Phase-I
 Phase I is the phase that includes the First-In-Human (FIH) trials within a small trial population (typically
<50 patients).
 The tested range of doses will usually be a fraction of the dose (1/100) that caused harm in animal tests.
 Comprises safety, tolerability and pharmacokinetics/dose ranging studies.
These studies are often conducted in healthy volunteers, but in some indications (for example, oncology) they
can include patients.
 Phase I trials are usually conducted in a clinical trial clinic, where the subject can be observed by full-time
staff. These clinical trial clinics are often run by CROs who conduct these studies on behalf of pharmaceutical
companies.
Phase I trials are subdivided into:
 Phase Ia:
In single ascending dose studies (SAD), small groups of subjects (3-5) are given a single dose
of the drug.
If they do not exhibit any adverse side effects, and the pharmacokinetic data are in line
with predicted safe values, the dose is escalated (X2), and a new group of subjects is then
given a higher dose.
This is continued until pre-calculated pharmacokinetic safety levels are reached, or
intolerable side effects start showing up (the drug is said to have reached the maximum
tolerated dose (MTD).
TGN1412, a monoclonal antibody is a TCR-independent agonist binding to CD28 present at the surface of CD4+ T-cells.
The phase-I trial conducted by Parexel was a double-blind, randomized, placebo-controlled study, with two of the eight
subjects receiving a placebo, and six receiving 0.1 mg per kg (1/500th of the highest dose found safe in preclinical
experiments with macaques).
Within half an hour all six subjects experienced a catastrophic systemic organ failure corresponding to a cytokine release
syndrome resulting in angioedema, swelling of skin and mucous membranes.
The therapeutic Index is a comparison of the amount of a therapeutic agent that causes the
therapeutic effect to the amount that causes toxicity.
A phase-I trial is not designed to evaluate the therapeutic effect
Phase I trials are subdivided into:
 Phase Ib:
In multiple ascending doses studies (MAD), a group of subjects receives multiple low doses
of the drug, while samples (of blood, urine …) are collected at various time points and
analyzed to acquire information on how the drug is processed within the body.
The dose is subsequently escalated.
Dose levels and dosing frequency are chosen in order to achieve steady state therapeutic
drug levels.
Phase-II
Phase II trials are aimed at evaluating the candidate drug’s efficacy in a patient population, leading up to
clinical proof of concept (PoC).
Phase II trials are also subdivided into Phase IIa and Phase IIb:
•
Phase IIa studies are generally smaller (typically <200 patients) and designed to mainly address
early evidence of drug activity and to assess dosing requirements.
• Phase IIb studies include larger numbers of patients (typically <400 patients) and are designed to
demonstrate clinical proof of concept and an understanding of dose response.
Genetic testing for polymorphic metabolism enzymes (Cyp2D6 or 2C9…), are performed particularly when
there is evidence of variation in metabolic rate between individuals.
Phase II clinical trials of ADX10059 (mGluR5 allosteric inhibitor)
in Gastro-Esophageal Reflux Disease (GERD)
Phase IIa trial:
Two days single-blind study in 24 patients.
Objectives: evaluate the effect of a single dose using
continuous 24-hour pH recording in the lower esophagus, and
on the occurrence of patient-recorded clinical symptoms of
GERD.
Phase IIb trial:
Two weeks of administration twice daily in 103 GERD patients.
Objectives: evaluate the effects on esophageal function and
reflux events using impedance pH monitoring and esophageal
manometry.
Phase-III
Phase III trials are designed to assess the effectiveness of the new drug and its value in clinical practice.
Phase III studies are randomized trials involving large patient groups (300–3,000 or more depending upon the
disease and the end points). Due to the difficulty in recruiting patients, they are in general multicenter trials.
Phase-III represent the definitive assessment of how effective the drug is, in comparison with the current
reference treatment (or a placebo if no approved reference treatment is available).
This assessment is based on the achievement of predetermined end-points:
“Results, condition or events associated with individual study patients that are used to assess study
treatments”. (FDA)
Primary end point: single endpoint parameter that will define the success or the failure of the drug.
Secondary end point(s): other endpoints pre-specified, may be powered for hypothesis testing
Direct Endpoints (FDA)
All drugs have safety risks.
Therefore, the only reason that a patient would want to take a drug would be if the drug:
– improved survival
– resulted in a benefit that was detectable by the patient (improvement in symptoms, in functional capacity), or
– decreased the chances of developing a condition or disease complication that is itself apparent to the patient
and is undesirable (e.g. stroke).
Therefore, a primary endpoint should be a direct measure of one of these.
A primary endpoint should generally not be a measure of something that is not important to the patient.
(exception: validated surrogate endpoint).
Surrogate endpoint – used instead of direct endpoint –
Ideally, the surrogate parameter should exist within the therapeutic pathway between the
drug and meaningful benefit – i.e. the drug results in the therapeutic benefit by virtue of
its effect on the surrogate parameter.
Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in
a clinically meaningful endpoint
ex hepatitis C: SVR-24 Sustained Viral Response (Detection of HCV RNA negative 24 weeks
after the end of treatment).
Hepatitis C Natural History
The full evolution of the disease takes 20 to 40 years
it is impossible to evaluate the success of a therapy on
direct clinical end-points.
http://www.sciencedirect.com.doc-distant.univ-lille2.fr/science/article/pii/S1521691812000923
Goal of hepatitis C treatment : Primary end-point
SVR 24: Detection of HCV RNA negative 24 weeks after 48 weeks of treatment.
Surrogate endpoint – used instead of direct endpoint –
Ideally, the surrogate should exist within the therapeutic pathway between the drug and
meaningful benefit – i.e. the drug results in the therapeutic benefit by virtue of its effect
on the surrogate
Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in
a clinically meaningful endpoint
• ex Cholesterol LDL Reduction as primary endpoint as opposed to a reduction in CV
morbidity or mortality
Phase-II: “A single-blind, placebocontrolled study to examine the effects of
torcetrapib, a potent inhibitor of CETP, on
plasma lipoprotein levels in 19 subjects
with low levels of HDL cholesterol”
Phase-III: “A randomized, double-blind study involving
15,067 patients at high cardiovascular risk.
The patients received either torcetrapib plus
atorvastatin or atorvastatin alone.
The primary outcome was the time to the first major
cardiovascular event.”
The trial was terminated prematurely
because of an increased risk of death and
cardiac events in patients receiving
torcetrapib.
Kaplan–Meier Curves for the Primary Composite Outcome
Phase-III: “A randomized, double-blind study involving
15,067 patients at high cardiovascular risk.
The patients received either torcetrapib plus
atorvastatin or atorvastatin alone.
The primary outcome was the time to the first major
cardiovascular event.”
Because of their size and comparatively
long duration, Phase III trials are the most
expensive, time-consuming and difficult
trials to design and run, especially in
therapies for chronic medical conditions.
A $800 million failure
Kaplan–Meier Curves for the Primary Composite Outcome
New Drug Submission (NDA) - Regulatory EMA / FDA
NATURE Drug Discovery vol 9 | March 2010 | 203
critical assessment of the pharmacologic,
pharmacokinetic, and toxicologic evaluation
chemical and
pharmaceutical data
critical assessment of
the clinical data
data summarisation and
integration
The Committee for Medicinal Products for Human Use concluded that the benefit/risk balance of DrugXXX is positive
The prescriber concludes that the benefit/risk balance of giving DrugXXX to patientYYY is positive
Discovery and development of a new molecular entity is a
highly inefficient process.
NATURE Drug Discovery vol 9 | March 2010 | 203
Discovery and development of a new molecular entity is a
highly inefficient process.
NATURE Drug Discovery vol 9 | March 2010 | 203
Virtual screening
100.000.000 compounds
High throughput Screening
1.000.000 compounds (mg)
Clinical trials
10 compounds (kg)
Animal Pharmacology
100 compounds (g)
attrition 9/10
Failures during discovery and development of a new molecular entity
O
CH3
N
N
N
O
O
O
NATURE Drug Discovery vol 9 | March 2010 | 203
irreversibility of the “prototype”
NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419
Results of a comprehensive longitudinal review of AstraZeneca’s small-molecule drug
projects from 2005 to 2010.
142 drug discovery and development projects at AstraZeneca.
The review covered projects from all therapeutic areas that had been active, from the
phases following the completion of preclinical research through to the end of clinical
testing in Phase II.
The key aims of the review were to understand the major reasons for project closure and
to identify the features of projects that correlated with successful outcomes.
Transition through proof of concept
(Phase II) is the area with the highest
rate of attrition.
In addition, it was significant lower
for Astra zenecca.
Success was defined as the percentage of
projects that moved from the indicated
phase to the next phase.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419
Safety was the major reason for project
closure in Preclinical phase (82%).
Efficacy was the major reason for project
closure in phase IIb (88%).
NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419
Safety
Safety: target organs
Major organ systems involved in preclinical and clinical safety closures.
Safety: on-target versus off-target
During preclinical testing, 75% of safety closures were
compound-related (due to ‘off-target’ actions other
than at the primary pharmacological Target)
By contrast, the proportion of target-related safety
closures rose substantially in the clinical phase and
was responsible for almost half of the safety-related
project closures.
Late failures were often due to a collapse in the
predicted margins between efficacious doses
and safety outcomes
Incidence of the level of confidence in preclinical safety profile
Projects
with preclinical
often
Level
of confidence
that safety
teams signals
had in their
closed owing
to safety
issues in the clinic.
preclinical
safety
profile.
Projects with minimal preclinical safety signals
rarely failed as a result of clinical safety issues.
Lack of efficacy
Efficacy was the major reason for project
closure in phase IIb (88%), where costs are
the highest.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419
Reasons for lack of clinical efficacy
1/ Target linkage to disease not established
40% of failed projects lacked data
demonstrating: a clear linkage of the target to
the disease
or access to a well-validated animal model of
the disease.
Projects that showed genetic target linkage to the
disease or a strong understanding of the role of
the target in the disease etiology were less likely
to fail owing to a lack of efficacy.
1/ Target linkage to disease not established
Human linkage data (even if functional) may
not be fully predictive of the validity of a
target.
For example, a naturally occurring human
variant of the CCR5 gene (CCR5-Δ32),
producing a non-functional receptor, was
negatively associated with rheumatoid
arthritis.
Preclinical models also supported the
therapeutic potential of this approach.
Nevertheless, several CCR5 antagonists
failed to show clinical benefit in patients
despite achieving exposure at the target
.
1/ Target linkage to disease not established
Availability of efficacy biomarkers at the start
of Phase II is a strong predictor of success
(82% versus 29%).
2/ Dose limited by compound characteristics
AZD3778, a dual CCR3 and H1-antagonist was developed for
the treatment of asthma.
AZD3778 inhibits the binding of a CCR3 radioligand, to the
CCR3-receptor expressed on CHO-cells with an IC50 of 8 nM.
From in vitro experiments on whole blood, of AZD3778, the A2
(the concentration required to produce a two-fold shift of the
agonist response) for CCR3 was 200 nM due to Plasma Protein
Binding.
In a proof-of-principle clinical trial, AZD 3778 had
undesirable pharmacokinetic properties with high protein
binding and a much shorter half-life than expected in
humans.
3/ Indication selected does not fit strongest preclinical evidence
Confidence in patient selection in Phase II-b:
High confidence in patient selection
positively correlated (90%) with active
projects in Phase IIb, whereas low
confidence in patient selection correlated
with project closures in the same phase
owing to a lack of clinical efficacy
Key factors underlying project failures
five key technical factors (the five Rs) were identified as substantial contributors to
project failures.
 the right target: the strength and quality of target validation
 the right tissue: demonstration of target engagement
 the right safety: reasonable safety margins
 the right patient: patient stratification plans
 the right commercial potential: the medical value proposition.
Right target: the importance of solid biological and disease understanding:
Direct evidence of target linkage to human disease,
Genetic evidence from animal models,
Understanding the biology underpinning the target and/or disease aetiology,
Confidence in preclinical and clinical data generated using animal models,
Data generated with tool compounds in the preclinical or clinical setting,
Validated efficacy biomarkers.
Right target: the importance of solid biological and disease understanding:
Preclinical data on anticoagulants intended to treat thrombosis or acute coronary syndrome have a high level of
confidence:
previous clinical experience
known validity and translation of the models,
confidence in the data generated from preclinical models
By contrast, target confidence in oncology, is low because based on screens with or poor translation to clinical outcomes
Such as subcutaneous tumour xenograft models that do not accurately replicate the human disease:
they often use immunocompromised animals;
the human tumour material is not introduced at the site of its primary source;
and, for many patients with cancer, morbidity is due to metastatic disease rather than the primary tumour.
Right tissue: appropriate pharmacokinetics/pharmacodynamics (PK/PD) modelling
Demonstration in both preclinical and clinical models, that the candidate drug achieved exposure in
the target organ and achieved sufficient pharmacological activity.
Appropriate understanding of PK/PD pharmacokinetic properties, together with the target
engagement and pharmacological activity relative to the target organ.
Right tissue:
appropriate pharmacokinetics/pharmacodynamics
(PK/PD) The greatest challenge occurs when the
pharmacological target and blood are separated by a
barrier, such as the blood– brain barrier.
The use of imaging techniques, particularly position
emission tomography (PET), to understand the
relationship between blood exposure, brain receptor
occupancy and efficacy has been effective in the
development of CNS-active drugs.
The use of biomarkers as inclusion or exclusion criteria, for enrolling patients into clinical studies has
increased dramatically since the sequencing of the human genome.
A REMS proposal may be required for New Drug Applications (NDAs), Biologic License Applications (BLAs),
Abbreviated New Drug Applications (ANDAs),
When “a risk evaluation and mitigation strategy is necessary to ensure that the benefits of the drug involved
outweigh the risks of the drug.”
The drug, which has been shown to be effective, but is associated with a serious adverse drug experience, can
be approved only if, or would be withdrawn unless, such elements are required as part of the REMS
“Elements to ensure safe use” may require that • Health care providers who prescribe the drug have particular training or experience or
are specially certified.
• Pharmacies, practitioners, or health care settings that dispense the drug are specially
certified
• The drug be dispensed to patients only in certain health care settings, such as hospitals.
• The drug be dispensed to patients with evidence or other documentation of safe use
conditions, such as lab results (ie pregnancy test).
• Each patient using the drug be subject to certain monitoring
• Each patient using the drug be enrolled in a registry
105
Alvimopan is a peripherally acting μ-opioid antagonist.
With limited ability to cross the blood–brain barrier, many
of the undesirable side-effects of the opioid agonists such
as constipation are minimized without affecting analgesia.
Alvimopan accelerates the gastrointestinal recovery period
and is approved for the treatment of postoperative ileus.
ENTEREG is available only to hospitals that perform surgeries that include a bowel resection and dispensed by
pharmacies that are enrolled in the E.A.S.E. ENTEREG REMS Program. This program is designed to ensure that ENTEREG is
used in accordance with the FDA-approved label and requires that:
• The E.A.S.E. ENTEREG REMS Program Kit has been received by the hospital and education on the benefits and risks of
ENTEREG has been provided to the healthcare practitioners who are responsible for ordering, dispensing, or
administration of ENTEREG.
• The certified hospital pharmacy has pharmacy systems, order sets, protocols, and/or other measures in place to limit
the use of ENTEREG to no more than 15 doses per patient for administration in the hospital inpatient setting only.
• The certified hospital pharmacy will not dispense ENTEREG for outpatient use and will not transfer ENTEREG to any
hospital pharmacy not enrolled with the E.A.S.E. ENTEREG REMS Program
• Healthcare professionals should report all suspected adverse events associated with the use of ENTEREG.
Prescriber and Pharmacist Information Brochure
http://www.enteregrems.com/pdf/ENTEREG%20REMS-Prescriber%20and%20Pharmacist%20Information%20Brochure.pdf
Sales for Praluent were about $12 million between July 2015 and February 2106 (9,500 prescriptions)
Repatha, sales totaled roughly $16 million and nearly between August 2015 and February 2016 (11,800 prescriptions)
Drug program phase transitions from 2006 to 2015 (7455 programs from 1103 companies)
Nature review DD 818 | DECEMBER 2016 | VOLUME 15